About PIK3CA
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PIK3CA c.412G>T, p.(Asp138Tyr)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen PIK3CA VCEP v1.1.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PP2Supporting
PP2 · supporting
PP2 is met at supporting strength because PIK3CA has a gnomAD missense constraint z-score of 8.75, which is greater than the Brain Malformations specification threshold of 3.09.
PM2Supporting
PM2 · supporting
PM2 is met at supporting strength because the variant is absent from both gnomAD v2.1 and gnomAD v4.1; the Brain Malformations specification defines PM2 for variants absent or rare in controls and does not provide a more granular quantitative cutoff beyond that statement.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
Brain Malformations VCEP qualitative combination
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: PIK3CA, the catalytic subunit of PI3-kinase, is frequently mutated in a diverse range of cancers including breast, endometrial and cervical cancers.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen PIK3CA VCEP v1.1.0, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 5 not met · 7 not assessed · 14 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_006218.4:c.412G>T (p.Asp138Tyr; p.D138Y) is absent from gnomAD v2.1 and gnomAD v4.1, which supports PM2 at supporting strength under the Brain Malformations specification.
PIK3CA is missense constrained, and the gnomAD missense z-score is 8.75, which is greater than the PP2 threshold of 3.09 defined in the specification.
Asp138 is outside the PIK3CA adaptor-binding domain (amino acids 31-108), Ras-binding domain (173-292), and kinase domains (322-483 and 797-1068) listed in Table 4, so PM1 is not supported.
ClinVar does not contain this variant, and no case-level, segregation, or functional evidence sufficient for PS1, PS2, PS3, PS4, PM5, BS3, PP1, BP2, or BP5 was available.
With PM2_supporting and PP2_supporting alone, the variant is classified as a variant of uncertain significance.
No criteria match.
Met · 2
PP2 SupportingPP2 is met at supporting strength because PIK3CA has a gnomAD missense constraint z-score of 8.75, which is greater than the Brain Malformations specification threshold of 3.09. Details ▾Hide ▴
Rule
Missense constraint computed in ExAC/gnomAD was utilized. Award PP2 if the z-score > 3.09. (applicable to MTOR, PIK3CA and AKT3 but not PIK3R2).
Evidence considered
- PIK3CA gnomAD missense z-score = 8.751433431539786.
- PP2 threshold in the specification is z-score > 3.09.
Sources
PM2 SupportingPM2 is met at supporting strength because the variant is absent from both gnomAD v2.1 and gnomAD v4.1; the Brain Malformations specification defines PM2 for variants absent or rare in controls and does not provide a more granular quantitative cutoff beyond that statement. Details ▾Hide ▴
Rule
Absent/rare from controls in an ethnically-matched cohort population sample (≥1).
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- PM2 is specified at supporting strength for variants absent/rare in controls.
Sources
Not met · 5 · evaluated, threshold not reached
BS2 The variant is absent from gnomAD v2.1 and gnomAD v4.1, so there are not at least 3 homozygotes to support BS2, and no well-phenotyped unaffected family data were provided. Details ▾Hide ▴
Rule
Award BS2 if ≥3 homozygotes present in gnomAD or ≥3 heterozygous in well phenotyped family members.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- BS2 requires at least 3 homozygotes in gnomAD or at least 3 heterozygotes in well-phenotyped family members.
Still missing
- No family-based unaffected carrier data were provided.
Sources
PM1 Asp138 lies outside the PIK3CA critical regions listed in Table 4 of the Brain Malformations specification: adaptor-binding domain amino acids 31-108, Ras-binding domain amino acids 173-292, and kinase domains amino acids 322-483 and 797-1068; therefore PM1 is not met. Details ▾Hide ▴
Rule
Residues affecting critical functional domains provided in Table 4 for each gene.
Evidence considered
- Table 4 critical domains for PIK3CA do not include residue 138.
Sources
vcep_c_l_i_n_g_e_n___b_r_a_i_n_m_a_l_f_o_r_m___a_c_m_g___s_p_e_c_i_f_i_c_a_t_i_o_n_s___v_1___1
PS4 No qualifying affected case evidence or literature-based point total was available, so PS4 was not met. Details ▾Hide ▴
Rule
PS4 strength is assigned by phenotype point totals and can only be used if PM2 is met.
Evidence considered
- PS4 in this framework requires phenotype-based case points and PM2.
- ClinVar search was negative for this variant.
- Literature packet contained no PMIDs.
Still missing
- No published or curated brain malformation cases with this variant were provided.
Sources
BA1 The variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed population frequency is 0 and does not exceed the BA1 threshold of greater than 0.0926%. Details ▾Hide ▴
Rule
Allele frequency (>0.0926%).
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- BA1 threshold is >0.0926%.
Sources
BS1 The variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed population frequency is 0 and does not exceed the BS1 threshold of greater than 0.0185%. Details ▾Hide ▴
Rule
Allele frequency (>0.0185%).
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- BS1 threshold is >0.0185%.
Sources
Not assessed · 7 · no assessment recorded
PS1 No established pathogenic variant producing the same amino acid change was documented in the case materials, so PS1 was not applied. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Evidence considered
- ClinVar search for this variant was negative.
Still missing
- A codon-level search for alternate nucleotide changes causing p.Asp138Tyr was not provided in the workspace.
Sources
PS2 No de novo or mosaic tissue-distribution data were provided to evaluate PS2 under the Brain Malformations specification. Details ▾Hide ▴
Rule
PS2_Strong requires Criteria 1 and 2; PS2_Moderate requires Criteria 1 or, if parents unavailable, Criteria 2.
Evidence considered
- PS2 requires parental absence and/or tissue mosaicism evidence under the specification.
Still missing
- Confirmed maternity/paternity data not provided.
- Affected-versus-unaffected tissue allele fraction data not provided.
Sources
BP5 No alternate molecular diagnosis was provided to support BP5. Details ▾Hide ▴
Rule
Variant found in a case with an alternate molecular basis for disease.
Evidence considered
- BP5 remains available but no alternate molecular basis was documented.
Still missing
- Case-level alternate molecular findings were not provided.
Sources
BP2 No cis/trans phasing data with another known pathogenic PIK3CA variant were provided, so BP2 was not assessed. Details ▾Hide ▴
Rule
Observed in cis or trans with a known pathogenic variant in the same gene.
Evidence considered
- BP2 requires observation in cis or trans with a known pathogenic variant.
Still missing
- No phasing data or second PIK3CA pathogenic variant reported.
Sources
BS3 No well-validated functional studies showing no damaging effect were provided, so BS3 was not applied. Details ▾Hide ▴
Rule
Follow recommendations set forth by the SVI in conjunction with specifications added by the Brain Malformation Group for quality metrics and minimum validation controls required.
Evidence considered
- BS3 requires validated functional evidence showing no damaging effect.
Still missing
- No benign functional assay data supplied.
Sources
PM5 No established pathogenic missense variant at codon 138 was documented in the supplied materials, so PM5 was not applied. Details ▾Hide ▴
Rule
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Evidence considered
- ClinVar search for this specific variant was negative.
Still missing
- A curated same-codon pathogenic comparator was not provided in the workspace.
Sources
PS3 No validated functional assay data meeting Brain Malformations VCEP requirements were provided, so PS3 was not applied. Details ▾Hide ▴
Rule
Follow recommendations set forth by the SVI in conjunction with specifications added by the BMVCEP for quality metrics and minimum validation controls required.
Evidence considered
- PS3 requires validated functional evidence under the Brain Malformations VCEP framework.
Still missing
- No acceptable functional assay evidence supplied.
Sources
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
BS4 N/ABS4 is designated not applicable by the Brain Malformations VCEP for this gene-disease framework. Details ▾Hide ▴
Rule
Not applicable as these are de novo, germline mosaic or post-zygotic mutations.
Evidence considered
- Brain Malformations VCEP marks BS4 not applicable.
Sources
PP4 N/APP4 is designated not applicable by the Brain Malformations VCEP because phenotype specificity is incorporated into PS4. Details ▾Hide ▴
Rule
Not applicable since this criterion is accounted for under PS4.
Evidence considered
- Brain Malformations VCEP marks PP4 not applicable.
Sources
PP3 N/APP3 is not applicable in this gain-of-function framework for PIK3CA. Details ▾Hide ▴
Rule
This criterion is not applicable since these variants are GOF, and traditional mutation pathogenicity prediction algorithms focus on LOF mechanisms.
Evidence considered
- Brain Malformations VCEP marks PP3 not applicable for these GOF genes.
Sources
PVS1 N/APVS1 is not applicable in this Brain Malformations VCEP framework because loss of function is not the established disease mechanism for these genes. Details ▾Hide ▴
Rule
LOF and/or haploinsufficiency have not been clearly identified as disease mechanisms underlying brain malformations related to these genes.
Evidence considered
- Brain Malformations VCEP marks PVS1 not applicable for these GOF genes.
Sources
PP5 N/APP5 is not used by this VCEP framework. Details ▾Hide ▴
Rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
- Brain Malformations VCEP marks PP5 not applicable.
Sources
BP7 N/ABP7 is limited to synonymous, certain intronic, and non-coding variants and is not applicable to this missense substitution. Details ▾Hide ▴
Rule
For synonymous, intronic positions (except canonical splice sites) and non-coding variants in the UTRs, if the nucleotide is non-conserved award this point.
Evidence considered
- Variant is missense p.Asp138Tyr.
Sources
BP4 N/ABP4 is restricted by this specification to synonymous, selected intronic, and non-coding variants, so it is not applicable to this missense variant despite a low SpliceAI score. Details ▾Hide ▴
Rule
Award BP4 for synonymous, intronic, or UTR variants when 2 of 3 splicing tools predict no impact; not applicable for other variant types.
Evidence considered
- Variant is missense.
- SpliceAI max delta score is 0.01.
Sources
BP3 N/ABP3 is designated not applicable by the Brain Malformations VCEP for these genes. Details ▾Hide ▴
Rule
This is not applicable for the genes specified since the exon regions do not have repetitive regions without a known function.
Evidence considered
- Brain Malformations VCEP marks BP3 not applicable.
Sources
BP1 N/ABP1 is not applicable because loss of function is not the relevant disease mechanism in this VCEP framework. Details ▾Hide ▴
Rule
Not applicable as LOF is not the disease mechanism.
Evidence considered
- Brain Malformations VCEP marks BP1 not applicable.
Sources
PP1 N/APP1 is designated not applicable by the Brain Malformations VCEP for this disorder framework. Details ▾Hide ▴
Rule
Not applicable since disease-causing variants are germline mosaic, de novo or mosaic.
Evidence considered
- Brain Malformations VCEP marks PP1 not applicable.
Sources
PM4 N/APM4 is not applicable in this VCEP framework. Details ▾Hide ▴
Rule
This point will not be used even though rare in-frame indels may result in GOF.
Evidence considered
- Brain Malformations VCEP marks PM4 not applicable.
Sources
PM3 N/APM3 is not applicable because the disorder mechanism in this framework is heterozygous rather than recessive. Details ▾Hide ▴
Rule
Not applicable since disease-causing variants are heterozygous.
Evidence considered
- Brain Malformations VCEP marks PM3 not applicable.
Sources
BP6 N/ABP6 is not used by this VCEP framework. Details ▾Hide ▴
Rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
- Brain Malformations VCEP marks BP6 not applicable.
Sources
PM6 N/APM6 is not used in this framework because de novo evidence is handled under PS2. Details ▾Hide ▴
Rule
This point is addressed according to PS2 and will not be used.
Evidence considered
- Brain Malformations VCEP marks PM6 not applicable.
Sources
Identifiers
- Gene
- PIK3CA
- Transcript
- NM_006218.4
- Coding (HGVS c.)
- NM_006218.4:c.412G>T
- Protein (HGVS p.)
- NP_006209.2:p.(Asp138Tyr)
- GRCh38
- chr3:179199749 G>T
- GRCh37
- chr3:178917537 G>T
Gene diagram
Every interpreted variant in PIK3CA, mapped onto the exon structure of NM_006218.4. Select a row to find it on the plot.
PIK3CANM_006218.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in PIK3CA
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/APP3 is not applicable in this gain-of-function framework for PIK3CA. Details ▾Hide ▴
Rule
This criterion is not applicable since these variants are GOF, and traditional mutation pathogenicity prediction algorithms focus on LOF mechanisms.
Evidence considered
- Brain Malformations VCEP marks PP3 not applicable for these GOF genes.
Sources
BP7 N/ABP7 is limited to synonymous, certain intronic, and non-coding variants and is not applicable to this missense substitution. Details ▾Hide ▴
Rule
For synonymous, intronic positions (except canonical splice sites) and non-coding variants in the UTRs, if the nucleotide is non-conserved award this point.
Evidence considered
- Variant is missense p.Asp138Tyr.
Sources
BP4 N/ABP4 is restricted by this specification to synonymous, selected intronic, and non-coding variants, so it is not applicable to this missense variant despite a low SpliceAI score. Details ▾Hide ▴
Rule
Award BP4 for synonymous, intronic, or UTR variants when 2 of 3 splicing tools predict no impact; not applicable for other variant types.
Evidence considered
- Variant is missense.
- SpliceAI max delta score is 0.01.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Cancer hotspots
Captured Cancer Hotspots source record
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/467907148
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_006218.4%3Ac.412G%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-178917537-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-179199749-G-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006218.4%3Ac.412G…
- OncoKB ↗www.oncokb.org/gene/PIK3CA/D138Y
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: PIK3CA, the catalytic subunit of PI3-kinase, is frequently mutated in a diverse range of cancers including breast, endometrial and cervical cancers.
Somatic
This variant has previously been reported in somatic cancers (COSMIC; COSV56030538, n = 2 times).